The present invention relates to the field of macrolide compounds having antibacterial activity, pharmaceutical compositions containing the compounds, and methods of treating bacterial infections with the compounds.
Erythromycins are well-known antibacterial agents widely used to treat and prevent bacterial infection caused by Gram-positive and Gram-negative bacteria. However, due to their low stability in acidic environment, they often carry side effects such as poor and erratic oral absorption. As with other antibacterial agents, bacterial strains having resistance or insufficient susceptibility to erythromycin have developed over time and are identified in patients suffering from such ailments as community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections. Particularly problematic pathogens include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin- and macrolide-resistant Streptococcus pneumoniae. Therefore, continuing efforts are called for to identify new erythromycin derivative compounds with improved antibacterial activity, and/or unanticipated selectivity against various target microorganisms, particularly erythromycin-resistant strains.
The following references relate to various erythromycin derivatives disclosed as having antibacterial activity:
EP 216,169 and U.S. Pat. No. 4,826,820 to Brain et al. disclose antibacterially active 6-carbamate erythromycin derivatives stated to xe2x80x9chave antibacterial properties, in particular against Gram-positive bacteria but also against some Gram-negative bacteria.xe2x80x9d
U.S. Pat. No. 5,444,051, U.S. Pat. No. 5,561,118, and U.S. Pat. No. 5,770,579, all to Agouridas et al., disclose erythromycin compounds such as those of the formula 
wherein substituents are as described in the respective references, which are all stated to be useful as antibiotics.
U.S. Pat. No. 5,866,549 to Or et al. and WO 98/09978 (Or et al.) disclose 6-O-substituted ketolides stated to have increased acid stability relative to erythromycin A and 6-O-methyl erythromycin A and enhanced activity toward gram negative bacteria and macrolide resistant gram positive bacteria.
WO 97/17356 (Or et al.) discloses tricyclic erythromycin derivatives stated to be useful in the treatment and prevention of bacterial infections.
WO 99/21871 (Phan et al.) discloses 2-halo-6-O-substituted ketolide derivatives of the formula 
wherein substituents are as described in the respective reference, which are stated to possess antibacterial activity.
WO 99/21864 (Or et al.) discloses 6,11-bridged erythromycin derivatives stated to have antibacterial activity.
WO 00/75156 (Phan et al.) discloses a 6-O-carbamate ketolide compound stated to be useful for treatment and prevention of infections in a mammal.
The invention provides compounds of Formula 1: 
wherein:
R1 and R2 are independently selected from hydrogen, optionally substituted C1-C8-alkyl, optionally substituted xe2x80x94CH2xe2x80x94C2-8alkenyl, and optionally substituted xe2x80x94CH2xe2x80x94C2-8alkynyl, wherein the substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, hydroxy, and C1-8alkoxy;
R3 is selected from hydrogen, OR4, SR4, and NR5R6, wherein R4, R5, and R6 are independently selected from the group consisting of C1-8alkyl, C3-8alkenyl, and C3-8alkynyl, said C1-8alkyl, C3-8alkenyl, and C3-8alkynyl being optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, and C1-6alkoxy;
R7 is hydrogen or a hydroxy protecting group; and
R8 is selected from hydrogen, alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C1-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl, heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl, C3-C6-cycloalkyl, C5-C8-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group;
or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt, esters or pro-drugs thereof.
Compounds of Formula 1 are useful as antibacterial agents for the treatment of bacterial infections in a subject such as human and animal.
The present invention is also directed to a method of treating a subject having a condition caused by or contributed to by bacterial infection, which comprises administering to said subject a therapeutically effective amount of the compound of Formula 1.
The present invention is further directed to a method of preventing a subject from suffering from a condition caused by or contributed to by bacterial infection, which comprises administering to the subject a prophylactically effective amount of the compound of Formula 1.
Other objects and advantages will become apparent to those skilled in the art from a review of the ensuing specification.
Relative to the above description, certain definitions apply as follows.
Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.
Unless specified otherwise, the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, and xe2x80x9calkynyl,xe2x80x9d whether used alone or as part of a substituent group, include straight and branched chains having 1 to 8 carbon atoms, or any number within this range. The term xe2x80x9calkylxe2x80x9d refers to straight or branched chain hydrocarbons. xe2x80x9cAlkenylxe2x80x9d refers to a straight or branched chain hydrocarbon with at least one carbonxe2x80x94carbon double bond. xe2x80x9cAlkynylxe2x80x9d refers to a straight or branched chain hydrocarbon with at least one carbonxe2x80x94carbon triple bound. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. xe2x80x9cAlkoxyxe2x80x9d radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. xe2x80x9cCycloalkylxe2x80x9d groups contain 3 to 8 ring carbons and preferably 5 to 7 ring carbons. The alkyl, alkenyl, alkynyl, cycloalkyl group and alkoxy group may be independently substituted with one or more members of the group including, but not limited to, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, xe2x80x94OCORa, xe2x80x94ORa, xe2x80x94SRa, xe2x80x94SORa, xe2x80x94SO2Ra, xe2x80x94COORa, xe2x80x94NRaRb, xe2x80x94CONRaRb, xe2x80x94OCONRaRb, xe2x80x94NHCORa, xe2x80x94NHCOORa, and xe2x80x94NHCONRaRb, wherein Ra and Rb are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl.
The term xe2x80x9cacylxe2x80x9d as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group. The term xe2x80x9cAcxe2x80x9d as used herein, whether used alone or as part of a substituent group, means acetyl.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means fluoro, chloro, bromo or iodo. (Mono-, di-, tri-, and per-)halo-alkyl is an alkyl radical substituted by independent replacement of the hydrogen atoms thereon with halogen.
xe2x80x9cArylxe2x80x9d or xe2x80x9cAr,xe2x80x9d whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2-naphthyl and the like. The carbocyclic aromatic radical may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with aryl, heteroaryl, halogen, OH, CN, mercapto, nitro, amino, C1-C8-alkyl, C2-C8-alkenyl, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-COxe2x80x94Oxe2x80x94, C1-C8-alkyl-COxe2x80x94NHxe2x80x94, or carboxamide. Illustrative aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. xe2x80x9cPhxe2x80x9d or xe2x80x9cPHxe2x80x9d denotes phenyl. xe2x80x9cBzxe2x80x9d denotes benzoyl.
Whether used alone or as part of a substituent group, xe2x80x9cheteroarylxe2x80x9d refers to a cyclic, fully unsaturated radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. The radical may be joined to the rest of the molecule via any of the ring atoms. Exemplary heteroaryl groups include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyi, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, N-oxo-pyridyl, 1,1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl-N-oxide, benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, indazolyl, indolizinyl, benzofuryl, cinnolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), imidazopyridinyl (such as imidazo[4,5-b]pyridinyl or imidazo[4,5-c]pyridinyl), naphthyridinyl, phthalazinyl, purinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, and thienothienyl. The heteroaryl group may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with aryl, heteroaryl, halogen, OH, CN, mercapto, nitro, amino, C1-C8-alkyl, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-COxe2x80x94Oxe2x80x94, C1-C8-alkyl-COxe2x80x94NHxe2x80x94, or carboxamide. Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1H-quinoline.
The terms xe2x80x9cheterocycle,xe2x80x9d xe2x80x9cheterocyclic,xe2x80x9d and xe2x80x9cheterocycloxe2x80x9d refer to an optionally substituted, fully saturated, partially saturated, or non-aromatic cyclic group which is, for example, a 4- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The nitrogen atoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolinyl; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl; thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone; 1,3-dioxolane; dioxanyl; thietanyl; thiiranyl; 2-oxazepinyl; azepinyl; and the like. Exemplary bicyclic heterocyclic groups include quinuclidinyl; tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl; benzothiopyranyl; dihydrobenzoth iopyranyl; dihydrobenzothiopyranyl sulfone; benzopyranyl; dihydrobenzopyranyl; indolinyl; chromonyl; coumarinyl; isochromanyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and the like.
Substituted aryl, substituted heteroaryl, and substituted heterocycle may also be substituted with a second substituted aryl, a second substituted heteroaryl, or a second substituted heterocycle to give, for example, a 4-pyrazol-1-yl-phenyl or 4-pyridin-2-yl-phenyl.
Designated numbers of carbon atoms (e.g., C1-C8 or C18) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
Unless specified otherwise, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
The term xe2x80x9chydroxy protecting groupxe2x80x9d refers to groups known in the art for such purpose. Commonly used hydroxy protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), which is incorporated herein by reference. Illustrative hydroxyl protecting groups include but are not limited to tetrahydropyranyl; benzyl; methylthiomethyl; ethythiomethyl; pivaloyl; phenylsulfonyl; triphenylmethyl; trisubstituted silyl such as trimethyl silyl, triethylsilyl, tributylsilyl, tri-isopropylsilyl, t-butyldimethylsilyl, tri-t-butylsilyl, methyldiphenylsilyl, ethyldiphenylsilyl, t-butyldiphenylsilyl; acyl and aroyl such as acetyl, benzoyl, pivaloylbenzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl and aliphatic acylaryl.
Where the compounds according to this invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
Some of the compounds of the present invention may have trans and cis isomers. In addition, where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers. The non-racemic forms may be obtained by either synthesis or resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. The compounds may also be resolved by covalent linkage to a chiral auxiliary, followed by chromatographic separation and/or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral chromatography.
The phrase xe2x80x9ca pharmaceutically acceptable saltxe2x80x9d denotes one or more salts of the free base which possess the desired pharmacological activity of the free base and which are neither biologically nor otherwise undesirable. These salts may be derived from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, or phosphoric acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, methyl sulfonic acid, salicyclic acid and the like. Suitable salts are furthermore those of inorganic or organic bases, such as KOH, NaOH, Ca(OH)2, Al(OH)3, piperidine, morpholine, ethylamine, triethylamine and the like.
Included within the scope of the invention are the hydrated forms of the compounds which contain various amounts of water, for instance, the hydrate, hemihydrate, and sesquihydrate forms. The present invention also includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
The term xe2x80x9csubjectxe2x80x9d includes, without limitation, any animal or artificially modified animal. As a particular embodiment, the subject is a human.
The term xe2x80x9cdrug-resistantxe2x80x9d or xe2x80x9cdrug-resistancexe2x80x9d refers to the characteristics of a microbe to survive in presence of a currently available antimicrobial agent such as an antibiotic at its routine, effective concentration.
The compounds described in the present invention possess antibacterial activity due to their novel structure, and are useful as antibacterial agents for the treatment of bacterial infections in humans and animals.
Preferably, compounds of Formula 1 wherein R1 and R2 are independently selected from hydrogen, substituted C1-8alkyl, optionally substituted xe2x80x94CH2xe2x80x94C2-8alkenyl, and substituted xe2x80x94CH2xe2x80x94C2-8alkynyl, wherein the substituents are selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, are embodiments of the present invention for such purposes. Particularly, R3 is hydrogen or OR4. Particularly, R7 is hydrogen. Particularly, R8 is ethyl.
Compounds of Formula 1 wherein R1 and R2 are independently selected from hydrogen and substituted xe2x80x94CH2xe2x80x94C2-8-alkenyl, wherein the substituents are substituted aryl or substituted heteroaryl, are preferred embodiments of the present invention. Particularly, R3 is hydrogen, and R1 and R2 are independently selected from hydrogen, (E)-3-[4-(2-pyrimidinyl)phenyl]-2-propenyl, (E)-3-[1-(2-pyrazinyl)-imidazol-4-yl]-2-propenyl, (E)-3-(4-isoquinolinyl)-2-propenyl, (E)-3-[1-(2-pyrimidinyl)-1H-imidazol-4-yl]-2-propenyl, and (E)-3-[3-(2-pyrimidinyl)phenyl]-2-propenyl.
The following compounds of Formula I are still preferred embodiments of the present invention, wherein
R3 is hydrogen or OR4, wherein R4 is C1-8 alkyl;
R7 is hydrogen;
R8 is ethyl; and
R1 and R2 are independently selected from hydrogen, substituted C1-C8-alkyl, optionally substituted xe2x80x94CH2C2-C8-alkenyl, and substituted xe2x80x94CH2C2-C8-alkynyl, wherein the substituents are selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
In particular, the following compounds are preferred embodiments of the present invention for such purposes: 




This invention also provides processes for preparing the instant compounds. The compounds of Formula I may be prepared from readily available starting materials such as erythromycin and erythromycin derivatives well known in the art. Outlined in Schemes 1 through 4 are representative procedures to prepare the compounds of the instant invention. Schemes 5 through 9 depict procedures to prepare key intermediates useful in the synthesis of compounds of the instant invention. 
Scheme 1 illustrates the method of synthesis of the 2xe2x80x2,4xe2x80x3,12-triacetyl-6-carbamyl-10,11-anhydroerythromycin A (VII: R=Ac) and 4xe2x80x3,12-diacetyl-2xe2x80x2-benzoyl-6-carbamyl-10,11-anhydroerythromycin A (VII: R=Bz) precursors to the compounds of the invention. Erythromycin A is treated with benzoic anhydride in the presence of a tertiary amine base, such as triethylamine, diisopropylethylamine, or pyridine, in a suitable solvent such as methylene chloride, chloroform, or THF (tetrahydrofuran) at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. for 2 to 72 hours to afford 2xe2x80x2-benzoylerythromycin A (II). The diacetyl derivative (III: R=Bz) can be obtained by treatment of II with acetic anhydride in the presence of a tertiary amine base, such as pyridine, triethylamine, or diisopropylethylamine, and an acylation catalyst, such as DMAP (4-(dimethylamino)pyridine), in a suitable solvent such as methylene chloride, chloroform, or THF at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. for 2 to 72 hours. Alternatively, the triacetyl derivative (III: R=Ac) may be obtained directly from erythromycin A by treatment with acetic anhydride in the presence of a tertiary amine base, such as triethylamine, diisopropylethylamine, or pyridine, and an acylation catalyst, such as DMAP, in a suitable solvent such as methylene chloride, chloroform, or THF at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. for 2 to 72 hours. The 10,11-anhydro derivative (IV) can be readily obtained by treatment of III with a base in an inert solvent such as THF, dioxane DME (1,2-dimethoxyethane), or DMF (dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to 80xc2x0 C. for 1 to 24 hours. Suitable bases to effect the elimination include, but are not limited to, sodium hexamethyldisilazide, potassium hexamethyldisilazide, LDA (lithium diisopropylamide), lithium tetramethylpiperidide, DBU (1,8-diazabicyclo[5.4.0]unded-7-ene), and tetramethylguanidine. It will be apparent to one skilled in the art that alternative methods for synthesis of 2xe2x80x2,4xe2x80x3-diacetyl-10,11-anhydroerythromycin A are available, including conversion of erythromycin A to the 11,12-cyclic carbonate derivative with ethylene carbonate, followed by elimination with tetramethylguanidine, as described in Hauske, J. R. and Kostek, G., J. Org. Chem. 1982, 47, 1595. Protection of the 2xe2x80x2 and 4xe2x80x3-hydroxyl groups can then be readily accomplished with acetic anhydride in the presence of a tertiary amine base. Similarly, access to 4xe2x80x3-acetyl-2xe2x80x2-benzoyl-10,11-anhydroerythromycin A from 10,11-anhydroerythromycin A could be accomplished through selective protection of the 2xe2x80x2-hydroxyl group as the benzoate derivative with benzoic anhydride in the presence of a tertiary amine base or alkali metal carbonate, followed by acetylation of the 4xe2x80x3-hydroxyl group with acetic anhydride in the presence of pyridine. Alternative protecting group strategies also could be envisaged, in which the 2xe2x80x2- and 4xe2x80x3-hydroxyl groups are differentially protected with acetyl, propionyl, benzoyl, formyl, benzyloxycarbonyl, or trialkylsilyl groups.
Once the suitably protected 10,11-anhydro derivative is obtained, acetylation of the 12-hydroxyl group to afford compound V can be accomplished by treatment with acetic anhydride in pyridine in the presence of a tertiary amine base, such as triethylamine or diisopropylethylamine, and an acylation catalyst, such as DMAP, at a temperature ranging from xe2x88x9220xc2x0 C. to 80xc2x0 C. for 2 to 72 hours. A suitable co-solvent, such as methylene chloride, chloroform, or THF may optionally be employed. Derivatization of the remaining tertiary hydroxy group can be carried out by treatment with trichloroacetylisocyanate in an inert solvent, such as methylene chloride, chloroform, or THF at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. for 1-24 hours to yield the N-trichloroacetylcarbamate (VI). The N-trichloroacetylcarbamate functionality can be hydrolyzed to the corresponding primary carbamate (VII) by treatment with a suitable base, such as 10% sodium hydroxide, in a biphasic solvent system, such as ethyl acetate/water, methylene chloride/water, and the like for 1-24 hours at a temperature ranging from 20xc2x0 C. to 80xc2x0 C. Alternative bases may likewise be used to effect this conversion, such as potassium hydroxide, sodium carbonate, potassium carbonate, or a tertiary amine base, such as triethylamine, in an aqueous solvent mixture. 
Scheme 2 depicts the synthesis of compounds of the instant invention represented by Formulae 1a and 1b, wherein RCCHO is an aldehyde (Rc may be a member of the group including, but not limited to, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkenyl, arylalkynyl, aralkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylalkyl, heterocycloalkenyl, heterocycloalkynyl, and heterocycloalkyl). The xcex3-lactone derivative (VIII) can be obtained by reaction of compound VII with a base in an inert solvent such as THF, dioxane, or DME at a temperature ranging from xe2x88x9278xc2x0 C. to 20xc2x0 C. for 1-24 hours. Suitable bases to effect this conversion include, but are not limited to, LDA, lithium tetramethylpiperidide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide. It will be recognized by one skilled in the art that in the conversion of VII to VIII two new stereocenters are formed, and consequently VIII may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step. Selective removal of the cladinose sugar can be accomplished by reaction of VIII with an acid, such as hydrochloric, sulfuric, chloroacetic, and trifluoroacetic, in the presence of alcohol and water to afford IX. Reaction time is typically 0.5-72 hours at a temperature ranging from xe2x88x9210xc2x0 C. to 37xc2x0 C. Oxidation of the 3-hydroxy group of IX to yield compound X can be effected with DMSO (dimethylsulfoxide) and a carbodiimide, such as EDCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), in the presence of pyridinium trifluoroacetate in a suitable solvent, such as methylene chloride, for 1 to 24 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. Alternative methods of oxidation include N-chlorosuccinimide and dimethylsulfide complex followed by treatment with a tertiary amine base, Dess-Martin periodinane, or oxalyl chloride/DMSO followed by treatment with a tertiary amine base. Removal of the 2xe2x80x2-acetyl group of compound X is readily accomplished by transesterification with methanol for 2-48 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 65xc2x0 C. to yield compound 1a. If the 2xe2x80x2-benzoyl group is optionally employed as the protecting group in compound X, its removal can be readily accomplished by transesterification with methanol for 2-72 hours at a temperature ranging from 20xc2x0 C. to 65xc2x0 C. to yield compound 1a. Alternate methods for deprotection of the 2xe2x80x2-acetyl or 2xe2x80x2-benzoyl group include hydrolysis in the presence of an alkali metal hydroxide or an alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol. Compounds of formula XI can be obtained by selective alkylation of the primary carbamate of X with a suitably substituted aldehyde or acetal in the presence of a reducing agent and acid. Preferred reagents for effecting this transformation are triethylsilane and trifluoroacetic acid in a suitable solvent, like acetonitrile, methylene chloride, or toluene at xe2x88x9220xc2x0 C. to 100xc2x0 C. Typically, the reaction is conducted for from 2-96 hours depending on the reactivity of the aldehyde or acetal. Compounds of formula 1b can then be obtained by removal of the 2xe2x80x2-acetyl or 2xe2x80x2-benzoyl group of compound XI, as described above for the conversion of X to 1a. Alternatively, compounds of formula 1b can be accessed directly from compounds of formula 1a by selective alkylation of the primary carbamate with a suitably substituted aldehyde in the presence of a reducing agent and acid, as described above for the conversion of X to XI. 
Scheme 3 depicts the synthesis of compounds of the instant invention of formula 1c, which contain a substituent (Rxe2x80x2) on the xcex3-lactone ring. As shown before, RdCHO is a suitably substituted aldehyde (Rd may be a member of the group including, but not limited to, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkenyl, arylalkynyl, aralkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylalkyl, heterocycloalkenyl, heterocycloalkynyl, and heterocycloalkyl). Compound IVxe2x80x2 is treated with a suitably substituted carboxylic acid derivative in the presence of a coupling reagent, such as DCC, and an acylation catalyst, such as DMAP, in a suitable solvent such as pyridine, methylene chloride, chloroform, or THF at a temperature ranging from xe2x88x9220xc2x0 C. to 62xc2x0 C. for 2-72 hours to afford compound XII. Alternative methods may also be employed to acylate the 12-hydroxy group, including reaction of compound IV with a pre-formed active ester derivative of the carboxylic acid, in the presence of an acylation catalyst, such as DMAP, in an inert solvent such as methylene chloride, chloroform, THF, or DMF. Suitable active ester derivatives include, but are not limited to, pentafluorophenyl, p-nitrophenyl, N-hydroxysuccinimide, and 3-hydroxy-3,4-dihydro-4-oxo-benzotriazine esters.
Derivatization of the remaining tertiary hydroxy group can be carried out by treatment with trichloroacetylisocyanate in an inert solvent, such as methylene chloride, chloroform, or THF at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. for 1-24 hours to yield the N-trichloroacetylcarbamate (XIII). The N-trichloroacetylcarbamate functionality can be hydrolyzed to the corresponding primary carbamate (XIV) by treatment with a suitable base, such as 10% sodium hydroxide, in a biphasic solvent system, such as ethyl acetate/water, methylene chloride/water, and the like for 1-24 hours at a temperature ranging from 20xc2x0 C. to 80xc2x0 C. Alternative bases may likewise be used to effect this conversion, such as potassium hydroxide, sodium carbonate, potassium carbonate, or a tertiary amine base, such as triethylamine, in an aqueous solvent mixture.
The xcex3-lactone derivative (XV) can be obtained by reaction of compound XIV with a base in an inert solvent such as THF, dioxane, or DME at a temperature ranging from xe2x88x9278xc2x0 C. to 20xc2x0 C. for 1-24 hours. Suitable bases to effect this conversion include, but are not limited to, LDA, lithium tetramethylpiperidide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide. It will be recognized by one skilled in the art that in the conversion of XIV to XV three new stereocenters are formed, and consequently XV may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or HPLC, or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step. Selective removal of the cladinose sugar can be accomplished by reaction of XV with an acid, such as hydrochloric, sulfuric, chloroacetic, and trifluoroacetic, in the presence of alcohol and water to afford XVI. Reaction time is typically 0.5-72 hours at a temperature ranging from xe2x88x9210xc2x0 C. to 37xc2x0 C. Oxidation of the 3-hydroxy group of XVI to yield compound XVII can be effected with DMSO and a carbodiimide, such as EDCI, in the presence of pyridinium trifluoroacetate in a suitable solvent, such as methylene chloride, for 1 to 24 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. Alternative methods of oxidation include N-chlorosuccinimide and dimethylsulfide complex followed by treatment with a tertiary amine base, Dess-Martin periodinane, or oxalyl chloride/DMSO followed by treatment with a tertiary amine base. Compounds of formula XVIII can be obtained by selective alkylation of the primary carbamate of XVII with a suitably substituted aldehyde or acetal in the presence of a reducing agent and acid. Preferred reagents for effecting this transformation are triethylsilane and trifluoroacetic acid in a suitable solvent, like acetonitrile, methylene chloride, or toluene at xe2x88x9220xc2x0 C. to 100xc2x0 C. Typically, the reaction is conducted for from 2-96 hours depending on the reactivity of the aldehyde or acetal. Compounds of formula 1c can then be obtained by transesterification of the 2xe2x80x2-benzoyl group of compound XVIII with methanol for 2-72 hours at a temperature ranging from 20xc2x0 C. to 65xc2x0 C. The final two steps of Scheme 3 may be conducted in reverse order in a manner analogous to Scheme 2 to provide compounds of the instant invention of formula 1c. 
Scheme 4 depicts the synthesis of compounds of the instant invention of formulae 1d and 1e. In compounds of formula 1e, Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Compound VIIxe2x80x2 is treated with allyl phenyl selenide in the presence of a suitable oxidizing agent, such as N-chlorosuccinimide, and a tertiary amine base, such as triethylamine or diisopropylethylamine, in a suitable nucleophilic solvent, such as methanol, at xe2x88x9220xc2x0 C. to 65xc2x0 C. for 2 to 48 hours to afford the N-allyl carbamate derivative (XIX). Under the reaction conditions, the 2xe2x80x2-acetoxy group undergoes methanolysis to yield the corresponding hydroxyl. Alternate reaction conditions may likewise be used to effect the conversion of VIIxe2x80x2 to XIX, such as reaction of compound VIIxe2x80x2 with a suitable allylating agent, such as t-butyl allyl carbonate, in the presence of a transition metal catalyst, such as tris(benzylideneacetone)dipalladium, and a suitable phosphine ligand, such as 1,4-bis(diphenylphosphino)butane, in an inert solvent, such as THF (see, for example, WO 00/75156). Reprotection of the 2xe2x80x2-hydroxyl group to give XX can be carried out by treatment with acetic anhydride in the presence of a tertiary amine base, such as triethylamine, diisopropylethylamine, or pyridine, and optionally an acylation catalyst, such as DMAP, in a suitable solvent such as methylene chloride, chloroform or THF at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. for 2 to 48 hours. The xcex3-lactone derivative (XXI) can be obtained by reaction of compound XX with a base in an inert solvent such as THF, dioxane, or DME at a temperature ranging from xe2x88x9278xc2x0 C. to 20xc2x0 C. for 1-24 hours. Suitable bases to effect this conversion include, but are not limited to, LDA, lithium tetramethylpiperidide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide. It will be recognized by one skilled in the art that in the conversion of XX to XXI two new stereocenters are formed, and consequently XXI may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or HPLC, or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step. Selective removal of the cladinose sugar can be accomplished by reaction of XXI with an acid, such as hydrochloric, sulfuric, chloroacetic, and trifluoroacetic, in the presence of alcohol and water to afford XXII. Reaction time is typically 0.5-72 hours at a temperature ranging from xe2x88x9210xc2x0 C. to 37xc2x0 C. Oxidation of the 3-hydroxy group of XXII to yield compound XXIII can be effected with DMSO and a carbodiimide, such as EDCI, in the presence of pyridinium trifluoroacetate in a suitable solvent, such as methylene chloride, for 1 to 24 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. Alternative methods of oxidation include N-chlorosuccinimide and dimethylsulfide complex followed by treatment with a tertiary amine base, Dess-Martin periodinane, or oxalyl chloride/DMSO followed by treatment with a tertiary amine base. Reaction of N-allyl carbamate (XXIII) with an aryl halide, a substituted aryl halide, a heteroaryl halide, or a substituted heteroaryl halide under Heck conditions with Pd(II) or Pd(0), a phosphine ligand, and a tertiary amine or inorganic base affords compounds of the instant invention 1d. Removal of the 2xe2x80x2-acetyl group of compound 1d is readily accomplished by transesterification with methanol for 2-48 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 65xc2x0 C. to yield compounds of the instant invention 1e. 
Scheme 5 depicts the synthesis of (E)-3-[5-(2-pyridinyl)-pyridin-3-yl]-2-propenal used in the preparation of Compound 11 and Compound 12). Reaction of 3,5-dibromopyridine (XXV) with chloro-2-pyridinylzinc under palladium catalysis conditions, in this case tris(benzylideneacetone)dipalladium and triphenylphosphine, in THF for 4 to 48 hours at 25xc2x0 C. to 62xc2x0 C. affords 3-bromo-5-(2-pyridinyl)pyridine (XXVI). Reaction of XXVI with tributyl[(1E)-3,3-diethoxy-1-propenyl]stannane (prepared as described in Parrain, J. L., Duchene, A., and Quintard, J. P., J. Chem. Soc., Perkin Trans. 1, 1990, 187), catalytic tris(benzylideneacetone)dipalladium and triphenylphosphine in DMF for 4 to 48 hours at 25xc2x0 C. to 80xc2x0 C., followed by hydrolysis with dilute hydrochloric acid for 15 minutes to 2 hours yields the desired aldehyde 2a. 
Scheme 6 illustrates the synthesis of certain of the aldehydes (2b) used in the preparation of compounds of the invention. Reaction of a bromocinnamaldehyde derivative (XXVII) with an aryl boronic acid to give the biaryl derivative (2b) is conducted under typical Suzuki coupling conditions, i.e., in the presence of a Pd0 catalyst, typically palladium tetrakistriphenylphosphine, and a base, typically sodium carbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, or triethylamine in a suitable solvent, such as toluene, ethanol, methanol, DME, or THF. Reaction time is typically 2 to 48 hours at a temperature ranging from 20xc2x0 C. to 110xc2x0 C. Aryl iodides and aryl triflates are also suitable substrates for this conversion. 
Scheme 7 illustrates a method of synthesis of certain of the aldehydes (2c) used in the preparation of compounds of the invention. Wittig-type reaction of an aromatic aldehyde (XXVIII) with 1,3-dioxolan-2-yl-methyltriphenylphosphonium bromide under phase transfer conditions in a biphasic solvent system in the presence of an inorganic base, such as potassium carbonate, affords the corresponding vinylogous aldehyde (2c). Th reaction is typically run from 2 to 48 hours at temperatures ranging from 0xc2x0 C. to 37xc2x0 C. The method is more fully described in Daubresse, N., Francesch, C. and Rolando, C., Tetrahedron, 1998, 54, 10761. 
Scheme 8 depicts the synthesis of 3-(3-pyridinyl)-2-propynal (2d) used in the preparation of Compound 18. Reaction of 3-bromopyridine with propargyl alcohol under typical Sonogashira coupling conditions, i.e., in the presence of a Pd0 or PdII catalyst, typically bis(acetonitrile)dichloropalladium (II), and an amine base, such as diisopropylethylamine, with a catalytic amount of copper(I) salt, typically copper iodide, and a phosphine ligand, such as tri-t-butylphosphine in a suitable solvent, such as THF, affords the desired 3-(3-pyridinyl)-2-propynal (XXXI). Reaction time is typically 2 to 72 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 62xc2x0 C. Oxidation of the alcohol derivative (XXXI) to the corresponding aldehyde (2d) can be readily carried out by treatment with manganese dioxide in a suitable solvent, such as methylene chloride, for 2 to 48 hours, at a temperature ranging from 0xc2x0 C. to 37xc2x0 C. Alternative reagents for oxidation of the alcohol can be contemplated, such as N-chlorosuccinimide and dimethylsulfide complex followed by a tertiary amine base, Dess-Martin periodinane, oxalyl chloride/DMSO followed by treatment with a tertiary amine base, or chromium-based oxidants, such as pyridinium chlorochromate or pyridinium dichromate. 
Scheme 9 illustrates the synthesis of 3-bromo-5-(2-pyrimidinyl)pyridine (3) used in the preparation of Compound 40. Reaction of 5-bromo-3-pyridine carboxamide (XXXII) with phosphorus oxychloride at temperatures ranging from 20xc2x0 C. to 106xc2x0 C. for 2 to 48 hours affords the corresponding nitrile. The nitrile is converted to the corresponding amidine (XXXIII) by first treating with gaseous hydrogen chloride and ethanol to obtain the imidate, and then reacting the imidate with ammonia, typically in an alcoholic solvent, such as methanol. The amidine may be isolated as the free base or an acid addition salt, preferrably the hydrochlride salt. Reaction of the amidine hydrochloride (XXXIII) with 1,1,3,3-tetramethoxypropane in a suitable solvent, such as dimethylformamide or N-methylpyrrolidinone, affords the desired 3-bromo-5-(2-pyrimidinyl)pyridine (3). Typically the reaction is carried out at temperatures ranging from 20xc2x0 C. to 110xc2x0 C. for 2 to 72 hours.
When the aldehydes, acetals, or aryl halides used in the preparation of compounds XI, XVIII, and XXIII are not commercially available, they can be obtained by conventional synthetic procedures, in accordance with literature precedent, from readily accessible starting materials using standard reagents and reaction conditions. Exemplary syntheses of several of the aldehydes used in the preparation of XI, XVIII, and XXIII are presented hereinafter as reference examples.
Compounds of the invention wherein R7 is a hydroxy protecting group other than acyl may be prepared in methods analogous to those shown in the above schemes with appropriate reagents that are either commercially available or may be made by known methods.
Compounds of the invention wherein the substituent at 13-position (i.e., R8) is a group other than ethyl may be prepared beginning with modified erythromycin derivatives as starting materials, such as those described in WO 99/35157, WO 00/62783, WO 00/63224, and WO 00/63225.
These compounds have antimicrobial activity against susceptible and drug resistant Gram positive and Gram negative bacteria. In particular, they are useful as broad spectrum antibacterial agents for the treatment of bacterial infections in humans and animals. These compounds are particularly activity against S. aureus, S. epidermidis, S. pneumoniae, S. pyogenes, Enterococci, Moraxella catarrhalis and H. influenzae. These compounds are particularly useful in the treatment of community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections.
Minimal inhibitory concentration (MIC) has been an indicator of in vitro antibacterial activity widely used in the art. The in vitro antimicrobial activity of the compounds was determined by the microdilution broth method following the test method from the National Committee for Clinical Laboratory Standards (NCCLS). This method is described in the NCCLS Document M7-A4, Vol.17, No.2, xe2x80x9cMethods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobicallyxe2x80x94Fourth Editionxe2x80x9d, which is incorporated herein by reference.
In this method two-fold serial dilutions of drug in cation adjusted Mueller-Hinton broth are added to wells in microdilution trays. The test organisms are prepared by adjusting the turbidity of actively growing broth cultures so that the final concentration of test organism after it is added to the wells is approximately 5xc3x97104 CFU/well.
Following inoculation of the microdilution trays, the trays are incubated at 35xc2x0 C. for 16-20 hours and then read. The MIC is the lowest concentration of test compound that completely inhibits growth of the test organism. The amount of growth in the wells containing the test compound is compared with the amount of growth in the growth-control wells (no test compound) used in each tray. As set forth in Table 1, compounds of the present invention were tested against a variety of Gram positive and Gram negative pathogenic bacteria resulting in a range of activities depending on the organism tested.
Table 1 below sets forth the biological activity (MIC, xcexcg/mL) of some compounds of the present invention.
This invention further provides a method of treating bacterial infections, or enhancing or potentiating the activity of other antibacterial agents, in warm-blooded animals, which comprises administering to the animals a compound of the invention alone or in admixture with another antibacterial agent in the form of a medicament according to the invention.
When the compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers, e.g., solvents, diluents, and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing for example, from about 0.5% to 5% of suspending agent, syrups containing, for example, from about 10% to 50% of sugar, and elixirs containing, for example, from about 20% to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.5% to 5% suspending agent in an isotonic medium. These pharmaceutical preparations may contain, for example, from about 0.5% up to about 90% of the active ingredient in combination with the carrier, more usually between 5% and 60% by weight.
Compositions for topical application may take the form of liquids, creams or gels, containing a therapeutically effective concentration of a compound of the invention admixed with a dermatologically acceptable carrier.
In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT (2,6-di-tert-butyl-4-methylphenol) and BHA (2-tert-butyl-4-methoxyphenol).
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred. These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacological acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.1 mg/kg to about 400 mg/kg of animal body weight, which may be given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 0.07 g to 7.0 g, preferably from about 100 mg to 2000 mg. Dosage forms suitable for internal use comprise from about 100 mg to 1200 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
The production of the above-mentioned pharmaceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredients(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).
The following examples describe in detail the chemical synthesis of representative compounds of the present invention. The procedures are illustrations, and the invention should not be construed as being limited by chemical reactions and conditions they express. No attempt has been made to optimize the yields obtained in these reactions, and it would be obvious to one skilled in the art that variations in reaction times, temperatures, solvents, and/or reagents could increase the yields.